Study on the Formation of Antihypertensive Twin Drugs by Caffeic Acid and Ferulic Acid with Telmisartan.

PURPOSE: This study aimed to synthesize twin drugs from cinnamic acid compounds, caffeic acid (CFA) and ferulic acid (FLA), which can antagonize endothelin-1 (ET-1) with telmisartan through ester bonds. Moreover, the antihypertensive effect of telmisartan and its influence on blood pressure variability (BPV) were enhanced, and the bioavailability of caffeic acid and ferulic acid was improved. METHODS: Six twin drugs, which were the target compounds, were synthesized. Hypertensive rats (SHR) and conscious sinoaortic-denervated (SAD) rats were spontaneously used as models for pharmacodynamic research to study the antihypertensive efficacy of these twin drugs. Wistar rats were employed as pharmacokinetic research models to investigate the pharmacokinetics of the target compounds via intragastric administration. Cellular pharmacodynamic research was also conducted on the antagonistic action on Ang II-AT1, ETA and ETB receptor. RESULTS: Compound 1a was determined as the best antihypertensive twin drug and thus was further studied for its effect on BPV. Compared with that of telmisartan, the antihypertensive effect of compound 1a was improved (p<0.05), and the BPV was reduced (p<0.05). The bioavailability of caffeic acid and ferulic acid after hydrolysis from twin drugs could be increased to varying degrees, and the differences of the main pharmacokinetic parameters among the different forms of caffeic acid and ferulic acid were statistically significant (p<0.05 or p<0.01). Compound 1a had the best antagonistic effect on the Ang II-AT1 receptor. However, the IC50 of Lps-2 was still two orders of magnitude higher than that of the positive drug telmisartan. Hence, the twin drugs worked by metabolizing and regenerating telmisartan and caffeic acid or ferulic acid in the body. CONCLUSION: The synthesized twin drugs improved telmisartan's antihypertensive effects, significantly decreased BPV in SAD rats and increased the bioavailability of caffeic acid and ferulic acid. This study serves as a basis for the development of new angiotensin receptor blocker (ARB) in the future and a reference for the development of new drugs to antagonize ET-1.

Synthesis, characterization and antihypertensive activity of 2-phenyl substituted benzimidazoles.

Hypertension is one of cardiovascular disease that is not sufficiently prevented and controlled at both hospital and community levels. Hypertension resulted in significant morbidity and mortality. The benz-imidazole ring is very important pharmacophore in modern drug discovery. The substituted benzimidazoles are the important for medicinal research. Researchers have reported that substituted Benzimidazoles are the structural isosteres of nucleotides, and easily allow them to interact with the different biopolymers, possess pharmacological activity especially antihypertensive activity. Angiotensin II Receptor Antagonists/Blockers (ARBs) compete with angiotensin II at the receptor site and block the contractile effect of angiotensin II in all vascular smooth muscles. Among all Angiotensin II Receptor Antagonists/Blockers (ARBs), Telmisartan, Milfasartan and many others have benzimidazole ring in their structure. In this study Angiotensin II Receptor Antagonists/Blockers (ARBs) have been prepared. Synthesized compounds were characterized by physical data and FTIR spectroscopic technique. Synthesized compounds studied were finally screened for their antihypertensive activity by tail cuff method of measurement of blood pressure by NIBP apparatus (None Invasive Blood Pressure) using Chart 5.0 software. The compounds synthesized were 2-(3-nitrophenyl)-1Hbenzimidazole (1a), 3-(1H benzimidazol-2-yl)aniline (1b) and 5-(1H-benzimidazol-2-yl)-2-methoxyphenol (1c). The synthesized compounds have shown antihypertensive activity by taking Losartan as lead compound.

N-Phenyl indole derivatives as AT1 antagonists with anti-hypertension activities: Design, synthesis and biological evaluation.

The design, synthesis, in vitro and in vivo evaluation of 6-substituted benzimidazole with 1, 4-disubsituted or 1, 5-disubsituted indole derivatives as novel angiotensin II receptor antagonists are outlined. Radioligand binding assays showed that several 6-substituted benzimidazole derivatives displayed high affinities binding to the angiotensin II type 1 receptor at the same order of magnitude to telmisartan. The biological evaluation on spontaneously hypertensive rats showed that 2-[4-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole-1-yl]methyl]-1H-indol-1-yl]benzoic acid, 1c, could cause significant decrease on MBP in a dose dependent manner. Its maximal response lowered 53 mmHg of MBP at 5 mg/kg and 64 mmHg of MBP at 10 mg/kg after oral administration, and the significant antihypertensive effect lasted beyond 24 h, which was better than both losartan and telmisartan. A study designed to determine acute toxicity showed that 1c had low acute toxicity with no significant changes in the weight and no obvious untoward reactions. The encouraging results make 1c an effective and durable anti-hypertension drug candidate and deserve further investigation for therapeutic application.

Discovery of novel, potent and low-toxicity angiotensin II receptor type 1 (AT1) blockers: Design, synthesis and biological evaluation of 6-substituted aminocarbonyl benzimidazoles with a chiral center.

Novel angiotensin II receptor type 1 (AT1) blockers bearing 6-substituted carbamoyl benzimidazoles with a chiral center were designed and synthesized as the first step to develop new antihypertensive agents and understand their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [(125)I] Sar(1) Ile(8)-Ang II, which was specifically bound to human AT1 receptor. Radioligand binding assays revealed nanomolar affinity in several compounds under study. The IC50 values of nine ligands were higher than those of Losartan. The screening of decreased blood pressure in spontaneous hypertensive rats displayed that compound 8S (IC50 = 5.0 nM) was equipotent with Losartan, whereas compounds 13R (IC50 = 7.3 nM), 14R (IC50 = 6.3 nM), and 14S (IC50 = 3.5 nM) were slightly ahead of Losartan, and the most significant activity was demonstrated by compound 8R (IC50 = 1.1 nM). Candidate 8R was identified for its excellent efficacy in antihypertension and fairly low toxicity based on plasma analyses, toxicology studies, and chronic oral tests. Finally, compound 8R exhibited strong and multiple interactions with target active sites of the theoretical AT1 receptor model in docking study.

Cobalt-catalyzed C-H arylations with weakly-coordinating amides and tetrazoles: expedient route to angiotensin-II-receptor blockers.

Cobalt-catalyzed C-H arylations enabled the synthesis of biaryl tetrazoles, which are key structural motifs in antihypertensive angiotensin-II-receptor blockers. Thus, weakly-coordinating benzamides were employed for step-economical C-H arylations with ample scope. Further, a low-valent NHC complex enabled first cobalt-catalyzed C-H functionalization by tetrazole assistance.

An efficient synthetic method and theoretical calculations of olmesartan methyl ether: study of biological function of AT1 antagonism.

The dissolution of the antihypertensive AT1 antagonist olmesartan in methanol generates in situ a new highly bioactive methyl ether analogue via SN1 mechanism involving an intramolecular proton transfer from carboxyl to hydroxyl group. Theoretical calculations confirmed the thermodynamic control preference of methyl ether versus the antagonistic product methyl ester. Α facile synthetic method for olmesartan methyl ether from olmesartan or olmesartan medoxomil is also described. Interestingly, the introduction of the methyl group to olmesartan did not alter its pharmacological properties. This observation opens new avenues in the synthesis of novel drugs, since hydroxyl and carboxylate groups have an orthogonal relationship in many drugs.

Synthesis and biological evaluation of a new angiotensin II receptor antagonist.

The design, synthesis, in vitro and in vivo evaluation of (2 R,6 S)-4-({1-[2-(1 H-tetrazol-5-yl)phenyl]-1 H-indol-4-yl}methyl)-2,6-dimethylmorpholine, compound 1, as a novel angiotensin II receptor antagonist is outlined. Radioligand binding assays showed that 1 displayed a high affinity for the angiotensin II type 1receptor with IC50 value of 0.82 nM. It acted as a potent anti-hypertensive derivative (maximal reduction of mean arterial pressure of 47 mm Hg at 10 mg/kg po in spontaneously hypertensive rat producing a dose-dependent fall in blood pressure following oral administration lasting beyond 10 h. Acute toxicity tests measured the LD50 of 1 value as 2431.7 mg/kg, which is higher than Losartan (LD50=2248 mg/kg). In addition further testing showed that 1 also demonstrated efficient anti-proliferative activity in vitro and anti-prostate cancer activity in vivo were also found. Taken together this compound could be considered as an effective and durable anti-hypertension drug candidate with additional anti-prostate cancer activity. These encouraging results are deserved of further investigation towards its use for therapeutic benefit.

Synthesis of a new series of angiotensin II receptor antagonists and antibacterial agents.

2-(Arylmethylenehydrazono)-4,4-diphenyl-1H-imidazol-5(4H)-one 3 underwent regioselective cyclization upon treatment with bromine in acetic acid containing sodium acetate to give the respective 3-substituted-6,6-diphenyl-6,7-dihydro-imidazo[2,1-c][1,2,4]triazole-5-one 4 in overall good yields and not the isomeric structure 5. In addition, compound 4 was synthesized by alternative method via reaction of compound 1 with different acids in acetic acid. The synthesized hydrazone derivatives were screened for their angiotensin II receptor antagonists activity and the results showed promising activity. Also, imidazo[2,1-c][1,2,4]triazole-5-ones 4 were screened for the antibacterial activity and the result revealed that two derivatives have excellent activity.

Synthesis and biological evaluation of new fluorine substituted derivatives as angiotensin II receptor antagonists with anti-hypertension and anti-tumor effects.

The synthesis and pharmaceutical activity of new potent non-tetrazole angiotensin II (Ang II) receptor antagonists were described. These compounds were fluorine substituted derivatives of Losartan, Valsartan and Irbesartan with carboxylic acid group as replacements to the known potent tetrazole moiety at the 2'-biphenyl position. Their activities were evaluated by Ang II receptor binding assay as well as by in vivo assay. All of the synthesized compounds showed nanomolar affinity for the AT(1) receptor subtype. The vivo biological evaluation showed that compounds 1a, 2 and 4 produced a dose-dependent antihypertensive effect both in spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR). Compound 4 especially showed an efficient and long-lasting effect in reducing blood pressure which can last more than 24 h at dose of 10 mg/kg in SHR, which was much better than control Losartan and Valsartan. Compound 4 can also inhibit the prostate cancer in vitro and in vivo. So compound 4 was selected for in-depth investigation as potent, novel and long-lasting non-tetrazole anti-hypertension and anti-tumor drug candidate.

Synthesis and biological evaluation of 4'-[(benzimidazole-1-yl)methyl]biphenyl-2-sulfonamide derivatives as dual angiotensin II/endothelin A receptor antagonists.

A series of 4'-[(benzimidazole-1-yl)methyl]biphenyl-2-sulfonamide derivatives (Ia-Il) were synthesized and biologically evaluated. It was found that Ig, the most active compound, antagonized both Ang II AT(1) and endothelin ET(A) receptors (AT(1) IC(50)=8.5, ET(A) IC(50)=8.9 nM), and was more potent than losartan in RHRs with no significant effect on heart rate. The preliminary structure-activity relationships were also discussed in the present paper.

Synthesis of angiotensin II receptor blockers by means of a catalytic system for C-H activation.

A highly efficient catalytic system for C-H activation has been worked out that involves inexpensive RuCl(3)·xH(2)O and a specific amount of PPh(3). This procedure has been successfully applied to a practical synthesis of angiotensin II receptor blockers (ARBs). The residual ruthenium that existed in the reaction mixture was thoroughly removed by treatment with properly selected metal scavengers. The new process permits ready access to the important class of drugs in a highly atom-economical and sustainable manner.

1-pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-pyrrolidine-2-carboxamide: investigation of structural variations.

We recently reported a series of 1-acyl-N-(biphenyl-4-ylmethyl)pyrrolidine-2-carboxamides as AT(1) receptor ligands. The most potent compound of the series, 1-pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-pyrrolidine-2-carboxamide, showed an interesting affinity for the receptor. To investigate the influence of structure variations on affinity, the synthesis of additional compounds belonging to this series has been performed. Biological tests run on the newly synthesized compounds on CHO-hAT(1) cells stably expressing the human AT(1) receptor confirm our previous hypothesis, i.e. that, within this series, the length of the acyl chain, the substitution of the amidic group and the nature of the acidic one are crucial for the receptor interaction, being a valeric chain, a secondary amidic function and the tetrazole moiety, respectively, the optimal ones.

Assessment of biological activity of novel peptide analogues of angiotensin IV.

OBJECTIVES: Angiotensin IV (Ang IV) is a metabolite of angiotensin II which acts on specific AT(4) receptors identified as the enzyme insulin regulated aminopeptidase (IRAP). The transduction process of these receptors is unresolved, but Ang IV inhibits the aminopeptidase activity. Ang IV improves cognition in animal models thus there is a desire to develop metabolically stable analogues for further development. METHODS: Peptide analogues of Ang IV were obtained commercially or synthesised. Each peptide was tested in vitro for its ability to inhibit the aminopeptidase activity (IRAP) of mouse brain homogenates and for its effects on isolated rat uterine smooth muscle. KEY FINDINGS: [Des-Val(1) ]-Ang IV, acetylated-Ang IV-amide, Ang IV-amide and [des-His(4) ]-Ang IV all inhibited IRAP. [Sar(1) , Ile(8) ]-Angiotensin II (10 µm) had an effect greater than that of Ang IV or any of the other analogues studied. In isolated uterine smooth muscle, angiotensins II and IV induced contractions, which could be antagonised by an AT(1) -receptor antagonist. None of the novel peptides induced uterine smooth muscle contractions, but [Sar(1) , des Arg(2) -Gly(8) ]-angiotensin II showed significant antagonism of the contractile effects of angiotensin II and carboxyamide-terminated Ang IV-NH(2) showed antagonism of Ang IV-induced contractions. CONCLUSIONS: This study provides five novel inhibitors of IRAP worthy of assessment in behavioural models of learning and memory. The analogues are devoid of AT(1) receptor agonist properties, and the carboxyamide analogue presents an opportunity to elucidate the mechanism of action of Ang IV as, like Ang IV, it inhibits IRAP, but antagonises the effects of Ang IV on isolated smooth muscle.

Synthesis and Antihypertensive Action of New Imidazo[1,2-a]pyridine Derivatives , non Peptidic Angiotensin II Receptor Antagonists.

The synthesis and antihypertensive activity of a group of imidazo[1,2-a]pyridine is described. New synthesized compound have been tested both in vivo and in vitro as antagonists on Angiotensin AT1 receptor, and compared to Losartan, used as reference drug. Binding assay an Angiotensin AT1 receptor were carried on as well. Compounds 6b and 6g showed a potent antihypertensive activity and an high affinity on AT1 receptor.

Towards non-peptide ANG II AT1 receptor antagonists based on urocanic acid: rational design, synthesis and biological evaluation.

A series of o-, m- and p-benzyl tetrazole derivatives 11a-c has been designed, synthesized and evaluated as potential Angiotensin II AT1 receptor antagonists, based on urocanic acid. Compound 11b with tetrazole moiety at the m-position showed moderate, however, higher activity compared to the o- and p-counterpart analogues. Molecular modelling techniques were performed in order to extract their putative bioactive conformations and explore their binding modes.

An efficient synthesis of a rationally designed 1,5 disubstituted imidazole AT(1) angiotensin II receptor antagonist: reorientation of imidazole pharmacophore groups in losartan reserves high receptor affinity and confirms docking studies.

A new 1,5 disubstituted imidazole AT(1) Angiotensin II (AII) receptor antagonist related to losartan with reversion of butyl and hydroxymethyl groups at the 2-, 5-positions of the imidazole ring was synthesized and evaluated for its antagonist activity (V8). In vitro results indicated that the reorientation of butyl and hydroxymethyl groups on the imidazole template of losartan retained high binding affinity to the AT(1) receptor concluding that the spacing of the substituents at the 2,5- positions is of primary importance. The docking studies are confirmed by binding assay results which clearly show a comparable binding score of the designed compound V8 with that of the prototype losartan. An efficient, regioselective and cost effective synthesis renders the new compound as an attractive candidate for advanced toxicological evaluation and a drug against hypertension.